rs1060502091

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001387283.1(SMARCA4):c.4891C>A(p.Leu1631Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1631F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.98

Publications

1 publications found

Variant links:

Genes affected

SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

SMARCA4 Gene-Disease associations (from GenCC):

Coffin-Siris syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
intellectual disability, autosomal dominant 16
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
rhabdoid tumor predisposition syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
uterine corpus sarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
familial rhabdoid tumor
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

SMARCA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.4891C>A	p.Leu1631Ile	missense_variant	Exon 35 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.4795C>A	p.Leu1599Ile	missense_variant	Exon 34 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SMARCA4	ENST00000646693.2 link	c.4891C>A	p.Leu1631Ile	missense_variant	Exon 35 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10 link	c.4795C>A	p.Leu1599Ile	missense_variant	Exon 34 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1 link	c.4801C>A	p.Leu1601Ile	missense_variant	Exon 34 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6 link	c.4705C>A	p.Leu1569Ile	missense_variant	Exon 34 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1 link	c.4705C>A	p.Leu1569Ile	missense_variant	Exon 33 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1 link	c.4705C>A	p.Leu1569Ile	missense_variant	Exon 33 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5 link	c.4702C>A	p.Leu1568Ile	missense_variant	Exon 34 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1 link	c.4216C>A	p.Leu1406Ile	missense_variant	Exon 31 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1 link	c.3445C>A	p.Leu1149Ile	missense_variant	Exon 27 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1 link	c.3427C>A	p.Leu1143Ile	missense_variant	Exon 26 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1 link	c.3289C>A	p.Leu1097Ile	missense_variant	Exon 26 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1 link	c.3055C>A	p.Leu1019Ile	missense_variant	Exon 24 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4 link	c.859C>A	p.Leu287Ile	missense_variant	Exon 7 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1403630

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

692824

African (AFR)

AF:

0.00

AC:

AN:

31760

American (AMR)

AF:

0.00

AC:

AN:

36018

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25202

East Asian (EAS)

AF:

0.00

AC:

AN:

35968

South Asian (SAS)

AF:

0.00

AC:

AN:

79730

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081624

Other (OTH)

AF:

0.00

AC:

AN:

58220

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2

Uncertain:1

Aug 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This sequence change replaces leucine with isoleucine at codon 1631 of the SMARCA4 protein (p.Leu1631Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Uncertain

0.52

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

1.4

L;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

4.0

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.98

N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.

REVEL

Uncertain

0.42

Sift

Benign

0.097

T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.

Sift4G

Benign

0.16

T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.

Polyphen

1.0

D;.;P;.;.;.;.;.;.;.;D;.;.;.;.;.;.;P;.;.;.;.

Vest4

0.42

MutPred

0.24

.;.;Gain of methylation at K1630 (P = 0.0463);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of methylation at K1630 (P = 0.0463);.;.;.;.;

MVP

0.64

MPC

2.2

ClinPred

0.90

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.48

Mutation Taster

=61/39

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over